Health News

Doctors use genetic code to make groundbreaking diagnosis

Albuquerque, N.M. — In work that advances medicine's ability to search our genes for the causes of disease, researchers from Wisconsin have sequenced a young boy's genes and pinpointed the genetic trigger of an illness that had baffled doctors.

The study, presented to 150 doctors and researchers at the annual meeting of the American College of Medical Genetics, follows a series of recent scientific papers exploring the potential of DNA sequencing as a tool to diagnose disease.

But unlike most of the papers, the Wisconsin case didn't stem from a scientific inquiry, but rather an attempt to help a very sick young boy.

"We went on quite an extensive hunting journey to try to find the cause," said David P. Dimmock, a pediatric genetic specialist at Children's Hospital of Wisconsin and assistant professor at the Medical College of Wisconsin. More than 10 doctors and researchers from the medical college and hospital joined in the work, which led to a new recommended treatment.

Dimmock said researchers started with a list of 2,000 candidate genes that might be responsible for the preschool boy's disease. DNA sequencing revealed that the culprit was not, in fact, one of those 2,000 genes.

"As far as I know, no one's used (this technique) in the way David has," said Michael Bamshad, professor and chief of genetic medicine in the pediatrics department at the University of Washington in Seattle.

The boy's first symptoms were an abscess at the opening of the rectum and poor weight gain. As his symptoms progressed, they resembled Crohn's disease, a type of inflammatory bowel disease.

But the disease resisted medications that usually help Crohn's patients and appeared to be much more severe. Instead of improving, the boy suffered formation of abnormal passageways between tissues called fistulas and blockages in his intestines. His wounds healed poorly. Ultimately, surgeons were forced to remove his colon.

And still they had no diagnosis for the child.

"In spite of everything we could throw at it, his disease progressed," Dimmock said.

Rather than sequencing the boy's entire genome, researchers used what they believed would be a more efficient route. They sequenced all of the approximately 23,000 genes in his genome, but only a portion of each gene, the exon. Exons contain the instructions for making different proteins. Proteins are essential parts of organisms and participate in virtually every process within cells. They are crucial to almost every human action from breathing to thinking, and many diseases result from a failure to make a protein correctly, or at all.

Although exons account for roughly 1% of the genome, they hold about 90% of the mutations that have significant effects, according to an editorial in The New England Journal of Medicine.

"The challenging part is sifting through these differences to find out the ones that matter," said Jay Shandure, assistant professor in the genome sciences department at University of Washington.

The Wisconsin researchers used a combination of powerful computing and human analysis to find the single mutation responsible for the boy's disease.

After sequencing the boy's exons, researchers compared the results with a "reference sequence," a standard model of the human genome produced by the Human Genome Project. The Wisconsin team found 16,124 differences between the boy's sequence and the reference sequence.

They narrowed those differences down to about 7,150 by considering redundancies in the genetic code - places where the DNA sequence can differ but still produce the same amino acid. Such changes are unlikely to cause disease.

Members of the Wisconsin team further whittled down the number by considering which of the remaining differences would end up altering a protein's structure or function in a significant way.

They were also able to eliminate mutations that were already known, since the researchers knew they were almost certainly looking at a mutation not previously identified. The team was finally able to settle on a mutation in one gene, and tests confirmed that this mutation was responsible for the child's illness.

The sequencing and analysis cost over $100,000, Dimmock said, and it took over five months to arrive at a diagnosis on Christmas Eve.

Researchers concluded the boy has a previously undocumented form of inflammatory bowel disease. Dimmock said sequencing the boy's DNA has led them to recommend re-booting his immune system through a bone marrow or umbilical cord stem cell transplant. That treatment has not been done yet.

Dian Donnai, a professor of medical genetics at the University of Manchester in England, praised the Wisconsin team's work as "fantastic" and "very exciting."